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PubMed2005

A unifying concept for assessing toxicological interactions: changes in slope.

Robust statistical methods are important to the evaluation of toxicological interactions (i.e., departures from additivity) among chemicals in a mixture. However, different concepts of joint toxic action as applied to the statistical analysis of chemical mixture toxicology data or as used in environmental risk assessment often appear to conflict with one another. A unifying approach for application of statistical methodology in chemical mixture toxicology research is based on consideration of change(s) in slope. If the slope of the dose-response curve of one chemical does not change in the presence of other chemicals, then there is no interaction between the first chemical and the others. Conversely, if the rate of change in the response with respect to dose of the first chemical changes in the presence of the other chemicals, then an interaction is said to exist. This concept of zero interaction is equivalent to the usual approach taken in additivity models in the statistical literature. In these additivity models, the rate of change in the response as a function of the i(th) chemical does not change in the presence of other chemicals in a mixture. It is important to note that Berenbaum's (1985, J. Theor. Biol. 114, 413-431) general and fundamental definition of additivity does not require the chemicals in the mixture to have a common toxic mode of action nor to have similarly shaped dose response curves. We show an algebraic equivalence between these statistical additivity models and the definition of additivity given by Berenbaum.

Complex Mixtures↗

PubMed2005

Research strategies for safety evaluation of nanomaterials, part II: toxicological and safety evaluation of nanomaterials, current challenges and data needs.

This article summarizes a roundtable discussion held at the 2005 Society of Toxicology Annual Meeting in New Orleans, LA. The purpose of the roundtable was to review the current challenges and data needs for conducting toxicological and safety evaluations for nanomaterials, with the goals of presenting the current state-of-the science on the safety of nanomaterials and bringing together scientists representing government, academia, and industry to identify priorities for developing data to facilitate risk assessments for these materials. In this summary, the unique physicochemical properties associated with nanomaterials are reviewed in the context of the difficulties associated with measuring and characterizing them. In addition, the development of appropriate hazard data, the collection of accurate human and environmental exposure information, and the development of a better fundamental understanding of the modes of action for nanomaterials are discussed as factors that will impact the development of comprehensive toxicological and safety evaluations.

Animals↗

PubMed1995

Mandatory toxicology testing and chemical dependence consultation follow-up in a level-one trauma center.

OBJECTIVE: There is a growing body of evidence indicating an association between intoxication and major trauma. This study assessed the prevalence of alcohol or drug intoxication in major trauma admissions to an urban trauma center. DESIGN: Sequential case series. METHODS: Toxicology testing and structural clinical interview assessment. MAIN RESULTS: Seventy-eight percent of patients tested had positive toxicology results. Chemical dependence assessments performed on patients who tested positive revealed that 94% met the criteria for a substance dependence or abuse disorder. CONCLUSIONS: The implications of this data for admission toxicology testing policies and chemical dependence consultation support services to trauma units are discussed.

Alcohol Drinking↗

PubMed2001

Epidemic increases in cocaine and opiate use by trauma center patients: documentation with a large clinical toxicology database.

BACKGROUND: Although reports have documented alcohol and other drug use by trauma patients, no studies of long-term trends have been published. We assessed substance use trends in a large cohort of patients admitted to a regional Level I adult trauma center between July 1984 and June 2000. METHODS: Positive toxicology results, collected via retrospective database review, were analyzed for patients admitted directly to the center. Data were abstracted from a clinical toxicology database for 53,338 patients. Results were analyzed for alcohol, cocaine, and opiates relative to sex, age (< 40/> or = 40 years), and injury type (nonviolence/violence). Positive toxicology test result trends were assessed for the 3 years at the beginning and end of the period (chi2). Testing biases were assessed for sex, race, and injury type. RESULTS: The patient profile was as follows: men, 72%; age < 40 years, 69%; nonviolence victims, 77%. Alcohol-positive results decreased 37%, but cocaine-positive and opiate-positive results increased 212% and 543%, respectively (all p < 0.001). Cocaine-positive/opiate-positive results increased 152%/640% for nonviolence and 226%/258% for violence victims, respectively (all p < 0.001). In fiscal year 2000, cocaine-positive and opiate-positive results were highest among violence victims (27.4% for both drugs). Cocaine-positive and opiate-positive results among nonviolence victims were 9.4% and 17.6%, respectively. Patients who were minorities or victims of violence were not tested more frequently than other patients. CONCLUSION: Epidemic increases in cocaine and opiate use were documented in all groups of trauma patients, with the greatest increases being in violence victims. Alcohol use decreased for all groups.

Adult↗

PubMed1996

Quality in environmental toxicology measurements.

From the clinical chemist's point of view, environmental toxicology can be defined as the identification or quantitation or both of environmental toxicants, their metabolites, and the biochemical consequences in easily accessible human specimens. Requirements as to specificity, accuracy, precision, and sensitivity will vary depending on the purpose of the analysis (e.g., diagnosis of acute intoxication vs. population baseline study). Laboratories must therefore clearly indicate the scope of their analytic methods. To ensure consistency of results, quality guidelines, such as International Standards Organization (ISO) guide 25, should be adhered to. However, to demonstrate accuracy, external proficiency assessment is required. Interlaboratory comparison programs, by using representative reference material, can document laboratory performance over time. Examples taken from the Quebec Toxicology Centre's program for toxic metals in biologic fluids indicate that laboratory performance has improved in recent years. The quality of results is generally adequate for most applications of environmental toxicology measurements.

Environmental Monitoring↗

PubMed2005

Toxicology screening results: injury associations among hospitalized trauma patients.

BACKGROUND: Substance abuse is associated with injuries, but these associations have not been well characterized by type of substance and injury type. METHODS: A cross-sectional study of patients selected for toxicology screening compared those with positive and those with negative test results for drugs and alcohol. RESULTS: Patients with positive alcohol toxicology results were more likely to have violence-related and penetrating injuries than patients with negative results. However, after adjustment for positive cocaine toxicology results, the association between alcohol and penetrating injury was no longer significant. Positive test results for any drug were not associated with any specific injury type, but cocaine was independently associated with violence-related injury. The associations of alcohol and cocaine with violence-related injury appear to be additive. In contrast, opiates were independently associated with nonviolent injuries and burns. CONCLUSIONS: Alcohol and cocaine use is independently associated with violence-related injuries, whereas opiate use is independently associated with nonviolent injuries and burns.

Adolescent↗

PubMed2002

Joint models for toxicology studies with dose-dependent number of implantations.

Many chemicals interfere with the natural reproductive processes in mammals. The chemicals may prevent the fertilization of an egg or keep a zygote from implanting in the uterine wall. For this reason, toxicology studies with pre-implantation exposure often exhibit a dose-related trend in the number of observed implantations per litter. Standard methods for analyzing developmental toxicology studies are conditioned on the number of implantations in the litter and therefore cannot estimate this effect of the chemical on the reproductive process. This article presents a joint modeling approach to estimating risk in toxicology studies with pre-implantation exposure. In the joint modeling approach, both the number of implanted fetuses and the outcome of each implanted fetus is modeled. Using this approach we show how to estimate the overall risk of a chemical that incorporates the risk of lost implantation due to pre-implantation exposure. Our approach has several distinct advantages over previous methods: (1) it is based on fitting a model for the observed data and, therefore, diagnostics of model fit and selection apply; (2) all assumptions are explicitly stated; and (3) it can be fit using standard software packages We illustrate our approach by analyzing a dominant lethal assay data set (Luning et al., 1966, Mutation Research, 3, 444-451) and compare ourresults with those of Rai and Van Ryzin (1985, Biometrics, 41,1-9) and Dunson (1998, Biometrics, 54, 558-569). In a simulation study, our approach has smaller bias and variance than the multiple imputation procedure of Dunson.

Abnormalities, Drug-Induced↗

PubMed2004

The Neuropsychopharmacology and Toxicology of 3,4-methylenedioxy-N-ethyl-amphetamine (MDEA).

This paper reviews the pharmacology and toxicology of 3,4-methylenedioxy-N-ethylamphetamine (MDEA, "eve"). MDEA is a ring-substituted amphetamine (RSA) like MDMA, its well known N-methyl analog. Both have become very popular substances of abuse in the techno- and house-music scene. They can evoke psychomotor stimulation, mild alterations of perception, sensations of closeness and a positive emotional state as well as sympathomimetic physical effects. At present, the name "ecstasy" is no longer used only for MDMA, but for the whole group of RSAs (MDA, MDMA, MDEA and MBDB) as they are chemically and pharmacologically nearly identical; moreover, many ecstasy pills contain mixtures of the RSAs. Hence, for a selective review on MDEA, it is crucial to strictly differentiate between: 1) street and chemical names, and 2) studies with or without chemically defined substances. In order to present MDEA-specific information, the pharmacodynamics and kinetics are described on the basis of MDEA challenge studies in animals and humans. In the toxicology section, we present a collection of case reports on fatalities where MDEA was toxicologically confirmed. On the question of serotonergic neurotoxicity and possible long-term consequences, however, MDEA-specific information is available from animal studies only. The neurotoxic potential of MDEA in humans is difficult to estimate, as ecstasy users do not consume pure substances. For future research, challenge studies in animals using dosing regimens adapted to human consumption patterns are needed. Such challenge studies should directly compare individual RSAs. They will represent the most viable and fruitful approach to the resolution of the highly controversial issues of serotonergic neurotoxicity and its functional consequences.

3,4-Methylenedioxyamphetamine↗

PubMed2006

Does blood donor history accurately reflect the use of prescription medications? A comparison of donor history and serum toxicologic analysis.

BACKGROUND: Blood donor screening is performed to accomplish several goals, including donor safety during collection and recipient safety during transfusion. Donors taking certain medications such as teratogens or platelet-inhibiting drugs are deferred from donation. Studies investigating the accuracy of the donor history are limited and only provide data on select groups of drugs. This study compares the results of an extended serum toxicology analysis to the medication use reported on the donor questionnaire. STUDY DESIGN AND METHODS: Whole-blood samples were collected from 108 volunteer blood donors. A serum toxicology analysis was performed with high-performance liquid chromatography with photodiode array detection. The results were compared to those reported on the donor history questionnaire. RESULTS: The medication history was consistent with the reported medications in 96 (89%) donors. Serum toxicology testing detected medications that were not reported on the donor history form in 12 (11%) donors. Most of the donors who did not accurately report their medication use (8 or 67%) were taking psychotropic medications. CONCLUSION: Eleven percent of the donors did not fully disclose their recent medication history. Although none of the omitted medications would have been grounds for deferral, the finding of underreporting questions the reliability of donor screening. Despite a negative medication history, blood donor centers cannot assume that donors are medication-free. This study reveals a bias to omit psychotropic medications such as antidepressants and anxiolytics.

Anti-Anxiety Agents↗

PubMed1994

The role of modulated gap junctional intercellular communication in epigenetic toxicology.

The normal development and health of all multicellular organisms, including the human being, depend on the adaptive maintenance of the integrity of the genetic information (e.g., DNA protective and repair mechanisms), as well as of the homeostatic and cybernetic regulatory systems within and between tissues. The primary focus of the past and current toxicological studies and risk assessment practices has been to ascertain and predict the "genotoxicity" of various physical and chemical agents. The paradigm of "carcinogen as mutagen," while valuable for stimulating studies of the detection of mutagens and of their potential role in "causing" somatic and germ line diseases, has tended to blunt research on the role of nongenotoxic mechanisms in disease causation. This brief analysis will emphasize the need to consider the role of modulated gap junctional intercellular communication (GJIC) in any biological risk assessment model. It is based on the following assumptions and facts. Because gap junctions exist in all metazoans, they have been associated with the regulation of cell proliferation, development, differentiation, and the adaptive function of both excitable and nonexcitable coupled cells. A highly evolutionarily conserved family of genes codes for proteins (connexins), which, as hexameric units (connexons), form membrane-associated channels of gap junctions. Cells coupled by gap junctions will have their ions and small regulatory molecules equilibrated. Regulation of GJIC can be at the transcriptional, translational, or posttranslational levels. Transient down or up regulation of GJIC can be induced by endogenous or exogenous chemicals via many mechanisms at any of these three levels. Stable abnormal regulation has been associated with activated oncogenes, and normal regulation has been associated with several tumor suppressor genes. The dysfunction of these gap junctions might play a role in the actions of various toxic chemicals that have cell type/tissue/organ specificity. This could bring about distinct clinical consequences, such as embryo lethality or teratogenesis, reproductive dysfunction in the gonads, neurotoxicity of the central nervous system, hyperplasia of the skin, and tumor promotion of initiated tissue. Modulation of GJIC should be viewed as a scientific basis of "epigenetic toxicology" because the alteration of intercellular communication would alter the internal physiological state of the cell. The inhibition of GJIC is a necessary component of mitogenesis (a necessary component of the multistage carcinogenic process). The modulation of GJIC can have both toxicological, as well as therapeutic potential.

Animals↗

PubMed1998

Genetic toxicology.

Systems for testing genetic toxicology are components of carcinogenic and genetic risk assessment. Present routine genotoxicity-testing is based on at least 20 years of development during which many different test systems have been introduced and used. Today, it is clear that no single test is capable of detecting all genotoxic agents. Therefore, the usual approach is to perform a standard battery of in-vitro and in-vivo tests for genotoxicity. Work-groups of the European Union (EU), the Organization for Economic Co-operation and Development (OECD), and, very recently, the work-group of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) have defined such standard battery tests. These and some currently used supplementary or confirmatory tests are briefly discussed here. Additional test systems for the assessment of genotoxic and carcinogenic hazard and risk are seriously needed. These tests must be more relevant to man than are current assays and less demanding in respect of cost, time and number of animals. Another aspect for reassessment derives from the actual situation in the pharmaceutical industry. Companies have to prepare for the world economy of the 21st century. Therefore, pharmaceutical research is speeding up tremendously by use of tools such as genomics, combinatorial chemistry, high throughput screening and proteomics. Toxicology and genotoxicology need to re-evaluate their changing environment and must find ways to respond to these needs. In conclusion, genetic toxicology needs to answer questions coming from two major directions: hazard and risk identification and high throughput testing.

Humans↗

PubMed1985

Toxicological assessment of lidocaine in the pregnant rat.

Teratogenic and toxicological effects of lidocaine administered during pregnancy were evaluated in the Sprague Dawley rat. High doses of lidocaine administered during specific periods of gestation were shown to produce no apparent adverse toxicological or teratogenic effects. Histological, enzymological, and physical features of the fetuses, utilizing conventional toxicological parameters, were all found to be normal following maternal administration of lidocaine. Analysis of these data suggests that the administration of lidocaine during pregnancy had no detectable adverse effects on the fetus.

Animals↗

PubMedDate not supplied

Absorption, metabolism, and other factors that influence drug exposure in toxicology studies.

Drug exposure in toxicology studies is dependent on input from the drug delivery system and elimination of the drug once absorbed. Although seemingly straightforward, absorption, metabolism, and other factors require a more complex interpretation of plasma concentrations and the resulting area under the plasma concentration versus time curve values at doses free from significant toxicity. Absorption may be saturable due to the intestinal, physiologic processes necessary for drug transfer, or intrinsic drug solubility limits may lead to a plateau in systemic plasma concentrations. Different vehicles or administration of drug with food or in the diet may be investigated in an effort to improve systemic exposure. Metabolic profiles may be examined to aid in the selection of a toxicology species more metabolically similar to humans. This will assist in providing adequate safety margins for metabolites as well as parent compound in comparison to humans. Safety assessment of drug metabolites has taken on added significance as our knowledge of metabolite pharmacokinetics in humans has increased. Correlation of free drug concentrations, determined in protein binding studies, may provide a better correlation with toxic effects than do total drug concentrations. Other factors, such as age, gender, and dosing interval need to be considered when interpreting toxicology studies.

Absorption↗

PubMedDate not supplied

Magnetic resonance microscopy--a new tool for the toxicologic pathologist.

Parallel to its many applications in medical imaging, magnetic resonance (MR) microscopy is a potentially powerful tool in toxicologic pathology. Because of the intrinsic qualities of MR microscopy (noninvasiveness, 3-dimensionality, and slicing in any chosen plane), the scientist has a new means by which to investigate different types of lesions based on differential contrast. By choosing appropriate proton stains to probe the state of the water in tissues, organ structure and vasculature can be seen and progressive lesion development can be followed in a given animal. This paper discusses toxicologic pathology applications for MR microscopy and compares MR microscopy with conventional histopathology using a time-course study of bromobenzene-induced hepatotoxicity in rats. Hematoxylin and eosin (H&E)-stained histological sections are compared with MR microscopy images from fixed tissue blocks to demonstrate one of the applications of MR microscopy to toxicologic pathology. The results indicate that MR microscopy is as sensitive as conventional H&E staining in detecting bromobenzene-induced hepatic lesions.

Animals↗

PubMed2006

Toxicological assessment of industrial solvents using human cell bioassays: assessment of short-term cytotoxicity and long-term genotoxicity potential.

There is an increasing demand for simple toxicological screening methods to assess the human health risk associated with exposure to environmental toxicants. Such screening tools should allow for risk evaluation in terms of both short-term/acute toxicity and longer-term genetic damage, which may lead to mutagenicity and carcinogenicity. We employed a battery of human cell bioassays using the human hepatoma cell-line, HepG2, to assess the cytotoxic and genotoxic potential of environmental pollutants. Here, we demonstrate direct application of these human cell bioassays to the toxicological assessment of a number of industrial solvents that are in common use worldwide. HepG2 cells were exposed to various solvents at concentrations ranging from 25 to 500 ppm. The cells were then analysed using specific protocols for four different adverse effects: cell death/acute cytotoxicity using a neutral red uptake assay, altered enzyme function (often an indicator of cell stress) using the ethoxyresorufin O-deethylase (EROD) bioassay, DNA single strand breaks (SSB), and DNA repair induction, which evaluates mutagenic activity. Using the positive controls, linear dose-response curves were achieved for all four bioassays. The high sensitivity of the tests allowed for environmentally meaningful assessments, and precision studies showed excellent reproducibility for all four bioassays. Comparing the results of the four bioassays on each of 16 industrial solvents allowed for ranking of the anticipated relative human toxicity of these solvents, which were comparable with data from standard toxicity tests and human occupational data. Overall, the study clearly supports the application of the HepG2 cell bioassay system for rapid toxicological screening of many candidate toxicants for both short- and long-term toxicity potential.

Biological Assay↗

PubMed1997

Toxicology of melatonin.

Despite the fact that melatonin has been released for public use in the United States by the Food and Drug Administration and is available over the counter nationwide, there currently is a total lack of information on the toxicology of melatonin. In Europe, melatonin has a completely different status in that it is considered a "neurohormone" and cannot be sold over the counter. Even though administration of melatonin in humans, as well as in animals (even at supraphysiological doses), has not shown evidence of toxicological effects (i.e., no deaths), a drug toxicological file still would need to be prepared and approved by the regulatory authorities. Several features that are specific to this neurohormone need to be taken into consideration. Whatever the species concerned, melatonin is secreted during the night; it is the "hormone of darkness." It presents a circadian rhythm and a circannual rhythm (in photoperiodic species). The duration of these secretions could have an impact on the reproductive system, for example, showing the importance of the pharmacodynamics of melatonin. An inappropriate time schedule of melatonin administration could induce supraphysiological concentrations of the neurohormone and a desensitization of melatonin receptors. A long duration of exposure to melatonin also could mimic an "artificial darkness" condition when a circadian rhythm with a basal zero level during the day needs to be conserved for a physiological function. Furthermore, administration of large doses of melatonin could induce high concentrations of melatonin and of different metabolites that could have deleterious effects per se. Numerous books, magazines, and articles have praised melatonin as a "miraculous cure-all" for ailments ranging from sleeplessness, to aging, without any clinical evidence of efficacy (with the exception of its chronobiotic and resynchronizing effect). Very little attention has been paid to the possible side effects of melatonin. Nightmares, hypotension, sleep disorders, abdominal pain, etcetera, have been reported. In fact, analysis of the known pharmacological profile of melatonin and/or of its metabolites, based on scientific preclinical studies, constitutes a basis for prediction of adverse drug reactions or side effects. These include (1) the central nervous system, (2) the cardiovascular system and platelet aggregation, (3) glucose metabolism, (4) immunology, and (5) cancer. The knowledge of the fundamental mechanism of action of melatonin, including molecular biology, also needs to be taken into account for evaluation of possible side effects. Two types of melatonin receptors have been cloned (related to cyclic AMP), and the possibility of intracellular action of melatonin cannot be excluded. Melatonin receptors are present in the periphery and also at the level of the central nervous system, particularly on the suprachiasmatic nucleus that "drives" a circadian rhythm to many other areas on which it projects. Among those, the hypothalamus (which has melatonin receptors) plays a fundamental role in the hormonal homeostasis and modulation control of the organism. Special preclinical and pharmacological studies that take into account all these parameters need to be designed for safety evaluation and risk assessment of this specific neurohormone.

Animals↗

PubMed1983

An investigation of the role of the specific opioid antagonist naloxone in clinical toxicology.

1 An assessment of the current role of naloxone in clinical toxicology has been made in a series of three separate epidemiological studies. 2 Through the National Poisons Information Service we found that the role of naloxone in opioid poisoning is often not appreciated by the enquirer and that toxicological screening is often requested before the diagnostic use of naloxone. 3 The recommended dose of naloxone (0.4--1.2 mg i.v.) is not always adequate. In 51 cases where naloxone was effective, doses of up to 3.2 mg were necessary (mean 1.8 +/- 0.3 mg SEM i.v.). 4 In 31 cases of non-opioid poisoning, naloxone in doses of 0.4--1.2 mg i.v. caused no deterioration, whilst six patients in whom no opioids were detected showed clinical improvement. 5 In 300 cases of suspected ethanol-induced coma, 49 showed reversal of coma with naloxone, and in 38 cases ethanol was the sole cause of coma (mean plasma concentration 3.54 +/- 0.62 g/l SEM). 6 These results suggest that the role of naloxone in clinical toxicology is not fully appreciated. There is a need for further education as to its indications in opioid poisoning, together with additional studies to define more accurately the dose/response relationship. In addition, the role of naloxone in coma induced by ethanol and certain other non-opioids needs to be evaluated further.

Alcoholic Intoxication↗

PubMed1991

Toxicology and the immune system: a perspective.

The relationship of immunology to toxicology has not always been an easy one, and the product of this association, immunotoxicology, has not infrequently been viewed with a certain scepticism by some of those who consider themselves 'classical' toxicologists. A recent meeting of the British Toxicology Society ('Toxicology and the Immune System', New College Oxford, March 21-22, 1991) provided an opportunity for some remedial work toward a wider appreciation of the issues which exercise immunotoxicologists, and the ways in which they are being addressed. It is not the purpose of this short article to provide a comprehensive account of the scientific presentations, but rather to give a perspective, necessarily a personal one, of immunotoxicology in the context of the meeting.

Humans↗